Fc gamma receptor IIIa polymorphisms in advanced colorectal cancer patients correlated with response to anti-EGFR antibodies and clinical outcome

Abstract

Background: Anti-EGFR monoclonal antibodies have shown efficacy in the treatment of metastatic colorectal cancer (mCRC). One of the mechanism is the antibody-dependent cell-mediated cytotoxicity (ADCC) in which Fc region of the antibody binds to the Fc gamma receptors (FcγR) expressed by immune cells. The present study investigated the association between single nucleotide polymorphisms of FcγRIIa and FcγRIIIa and clinical outcome in mCRC treated with anti-EGFR antibodies.

Methods: Seventy-four consecutive patients with mCRC were analyzed. The genotypes for FcγRIIa-131 histidine (H)/arginine (R), FcγRIIIa-158 valine (V)/phenylanaline (F) polymorphisms were evaluated by directly sequencing. Multiplex allele-specific polymerase chain reaction was performed for FcγRIIIa-158 valine (V)/phenylanaline (F). Correlations between FcγR polymorphisms, baseline patient and tumor features were studied by contingency tables and the chi-square test. The Kaplan-Meier product limit method was applied to the progression-free survival (PFS) curves. Univariate analysis was performed with the log-rank test. Cox proportional-hazards regression was used to analyze the effect of multiple risk factors on PFS.

Results: FcγRIIIa polymorphisms were significantly associated with response to anti-EGFR-based therapy in 49 patients with kras wt tumors (p=0.035). There was not association with response for FcγRIIa polymorphisms. Furthermore, obtained results suggested that prognosis is particularly unfavorable for patients carrying the FcγRIIIa-158F/F genotype (median PFS V/V, V/F, F/F: 18.2 vs 17.3 vs 9.4 months). No prognostic ability was identified for FcγRIIa polymorphisms.

Conclusions: In mCRC patients the presence of FcγRIIIa-F can predict resistance to anti-EGFR therapy and unfavorable prognosis.

Figure 1

FcγRIIa determined by direct sequencing and FcγRIIIa allotyping by allele-specific PCR. v Upper Panel. FcγRIIa determined by direct sequencing: (a) Sequencing electropherogram obtained from a sample homozygous for allele FcγRIIa 131H/H; (b) Sequencing electropherogram obtained from a sample heterozygous for allele FcγRIIa 131H/R; (c) Sequencing electropherogram obtained from a sample homozygous for allele FcγRIIa 131R/R. Lower Panel. FcγRIIIa allotyping by allele-specific PCR. 100bp ladder marker, FcγRIIIa genotypes direct sequenced F/F, V/F and V/V control and CTL- negative control were represented. Examples represented respectively F/F (a), V/F (b) and V/V (c) patients.

Figure 2

Progression-free survival curves according to FcγR polymorphisms on 49 mCR Cpatients. Progression-free survival was defined as time elapsed between treatment initiation and tumor progression (a) FcγRIIa: median PFS was 16.1 months in H/H patients (18 patients, 13 events) vs 18.2 months in H/R patients (27 patients, 23 events) vs 13.3 months in R/R patients (4 patients, 3 events); Log Rank test for three curves: p = 0.61. (b) FcγRIIIa: median PFS was 18.2 months in V/V patients (18 patients, 13 events) vs 17.3 months in V/F patients (26 patients, 25 events) vs 9.4 months in F/F patients (5 patients, 5 events); Log Rank test for three curves: p = 0.04.